Neurofibromatosis type 1 (NF1) is characterized by skeletal abnormalities such as scoliosis, fragility, fractures and pseudoarthrosis (failure of bones to fuse properly after fractures). The disorder is caused by mutations of neurofibromin, a protein that regulates cellular signaling pathways. New research from investigators at Vanderbilt University (Nashville, TN) suggests that treatment with the enzyme asfotase-α prevents skeletal defects in a mouse model of NF1 by increasing bone growth, mineralization and strength. Florent Elefteriou, who led the study, hopes the work will lead to treatments for people with NF1, many of whom are children. Currently, skeletal anomalies are managed by invasive and often repeated surgical intervention, which is not only painful but also limited to correction of bone abnormalities. Elefteriou and his group sought a strategy that could prevent bone defects from occurring at all. But first, they needed to understand the mechanism underlying abnormal skeletal development in the absence of neurofibromin.

Elefteriou and his colleagues studied the molecular pathology of skeletal defects in NF1 using a mouse model. They observed poor matrix mineralization in bone tissue from mice lacking neurofibromin, a condition called hyperosteoidosis, which was caused by accumulation of pyrophosphate, an inhibitor of bone mineralization. In the absence of neurofibromin, the expression of genes that promote synthesis and transport of pyrophosphate was upregulated. In addition, bone progenitor cells failed to differentiate properly into osteoblasts and did not produce alkaline phosphatase, an enzyme that normally breaks down pyrophosphate, further contributing to the accumulation of pyrophosphate and its consequent inhibition of bone mineralization.

The investigators wondered whether eliminating the accumulated pyrophosphate could improve bone mineralization. They treated NF1 model mice with asfotase-α, a recombinant form of alkaline phosphatase that is being tested for the treatment of hypophosphatasia, another rare genetic disease affecting bone formation. Treatment with asfotase-α improved bone mass, mineralization and mechanical properties in the mice (Nat. Med. 20, 904–910; 2014).

Elefteriou's group also examined pseudoarthrosis samples from people with NF1 and found upregulated expression of one of the genes promoting pyrophosphate synthesis, suggesting that NF1 pathology is similar in humans and mice and, therefore, that asfotase-α might be effective for improving bone strength in people with the disease. Elefteriou hopes that “we can make bone stronger and better by injecting this drug, and possibly prevent fractures in patients with neurofibromatosis,” he said in a news release. “It's exciting that instead of fixing the bones after they break, we might have a drug now to prevent the fractures.”